Crystalline Form Of A Cyclopropyl Benzamide Derivative

ABSTRACT

The present invention relates to a crystalline form of compound (I), 4-{(1S,2S)-2-[(4-cyclobutylpiperazin- 1 -yl)carbonyl]-cyclopropyl}-benzamide, 
     
       
         
         
             
             
         
       
     
     pharmaceutical formulations containing said compound and to the use of said active compound in therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/305,583, filed Feb. 18, 2010, the entirety of which is incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to crystalline forms of a compound (I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,particularly such as Form I, pharmaceutical formulations containing saidcompound and to the use of said active compounds in therapy.

BACKGROUND OF THE INVENTION

The crystalline forms of4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamideare useful to treat at least one histamine H3 receptor associatedcondition.

The histamine H3 receptor is of current interest in developing newmedicaments. The H3 receptor is a presynaptic autoreceptor located bothin the central and peripheral nervous systems, the skin, and in organs,such as, for example, the lung, the intestine, probably the spleen, andthe gastrointestinal tract. Recent evidence suggests the H3 receptor hasintrinsic, constitutive activity in vitro as well as in vivo (i.e., itis active in the absence of an agonist). Compounds acting as inverseagonists can inhibit this activity. The histamine H3 receptor has beenshown to regulate the release of histamine and also of otherneurotransmitters, such as, for example, serotonin and acetylcholine.Some histamine H3 ligands, such as, for example, a histamine H3 receptorantagonist or inverse agonist may increase the release ofneurotransmitters in the brain, whereas other histamine H3 ligands, suchas, for example, histamine H3 receptor agonists may inhibit thebiosynthesis of histamine, as well as, inhibit the release ofneurotransmitters. This suggests that histamine H3 receptor agonists,inverse agonists, and antagonists could mediate neuronal activity. As aresult, efforts have been undertaken to develop new therapeutics thattarget the histamine H3 receptor.

WO2009/024823 describes the synthesis of a number of cyclopropyl amidederivatives, such as, for example,4-((trans)-2-[(4-cyclobutylpiperazin-yl)carbonyl]-cyclopropyl}-benzamide(enantiomer 1; Example 43).

DETAILED DESCRIPTION OF THE INVENTION

One object of the present invention is to provide crystalline forms ofcompound (I), 4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide.

Another object of the present invention is to provide a crystalline formof compound (I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,as Form I.

Said compound (I) having a histamine receptor antagonist or inverseagonist effect at the H3 receptor which making them suitable to beformulated into pharmaceutical is formulations.

Accordingly, the present invention provides a crystalline form ofcompound (I), 4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide

One aspect of the invention relates to a crystalline form of compound(I), characterized in that said form has an XRDP pattern (Cu Kα) with atleast one peak at about 18.3 °2Theta, when measured using radiation witha wavelength of about 1.54 angstroms.

Another aspect of the invention relates to a crystalline form ofcompound (I), characterized in that said form has an XRDP pattern (CuKα) with at least two peaks at about 4.9 and about 18.3 °2Theta, whenmeasured using radiation with a wavelength of about 1.54 angstroms.

Yet another aspect of the invention relates to a crystalline form ofcompound (I), characterized in that said form has an XRDP pattern (CuKα) with at least three peaks at about 4.9, about 18.3 and about 20.4°2Theta, when measured using radiation with a wavelength of about 1.54angstroms.

Still another aspect of the invention relates to a crystalline form ofcompound (I), characterized in that said form has an XRDP pattern (CuKα) with at least four peaks at about 4.9, about 18.3, about 19.6 andabout 20.4 °2Theta, when measured using radiation with a wavelength ofabout 1.54 angstroms.

A further aspect of the invention relates to a crystalline form ofcompound (I), characterized in that said form has an XRDP pattern (CuKα) with peaks at selected °₂Theta-values described above and withadditional peaks at about 16.4 and about 16.6, °2Theta when measuredusing radiation with a wavelength of about 1.54 angstroms.

Yet a further aspect of the invention relates to a crystalline form ofcompound (I), characterized in that said form has an XRDP pattern (CuKα) with peaks at selected °2Theta-values described above and with anadditional peak at about 5.3 °2Theta, when measured using radiation witha wavelength of about 1.54 angstroms.

Still a further aspect of the invention relates to a crystalline form ofcompound (I), characterized in that said form has an XRDP pattern (CuKα) with peaks at °2Theta-values selected from about 4.9, about 16.4,about 16.6, about 18.3, about 19.6 and about 20.4, when measured usingradiation with a wavelength of about 1.54 angstroms.

Still a further aspect of the invention relates to a crystalline form ofcompound (I), characterized in that said form has an XRDP pattern (CuKα) with peaks at °2Theta-values selected from about 4.9, about 5.3,about 16.4, about 16.6, about 18.3, about 19.6 and about 20.4, whenmeasured using radiation with a wavelength of about 1.54 angstroms.

Still a further aspect of the invention relates to a crystalline form ofcompound (I), characterized in that said form has an XRDP pattern (CuKα) with peaks at °2Theta-values selected from about 4.9, about 12.6,about 16.4, about 16.6, about 18.3, about 19.6, about 20.4, and about23.2, when measured using radiation with a wavelength of about 1.54angstroms.

Still a further aspect of the invention relates to a crystalline form ofcompound (I), characterized in that said form has an XRDP pattern (CuKα) with peaks at °2Theta-values selected from about 4.9, about 5.3,about 9.0, about 12.6, about 16.4, about 16.6, about 18.3, about 19.6,about 20.4, and about 23.2, when measured using radiation with awavelength of about 1.54 angstroms.

Still a further aspect of the invention relates to a crystalline form ofcompound (I), is characterized in that said form has an XRDP pattern (CuKα) with peaks at from about 4.9, about 5.3, about 9.0, about 12.6,about 16.4, about 16.6, about 18.3, about 19.6, about 20.4, about 21.2,about 23.2 and about 24.6 °2Theta, when measured using radiation with awavelength of about 1.54 angstroms.

Yet still a further aspect of the invention relates to relates to acrystalline form of compound (I), characterized by the X-ray powderdiffraction pattern essentially as shown in FIG. 1.

Another embodiment relates to a crystalline form of compound (I) thathas a DSC thermogram essentially as depicted in FIG. 2.

In another embodiment, a crystalline form of compound (I) has a DSCthermogram comprising an endothermic event with an onset temperature ofabout 225° C.

In still another embodiment, a crystalline form of compound (I) has aDSC thermogram comprising an endothermic event with a peak temperatureof about 235° C.

It is well known that the DSC onset and peak temperatures as well asenergy values may vary due to, for example, the purity of the sample andsample size and due to instrumental parameters, especially thetemperature scan rate. Hence the DSC data presented are not to be takenas absolute values. A person skilled in the art can set up instrumentalparameters for a Differential scanning calorimeter so that datacomparable to the data presented here can be collected according tostandard methods, for example those described in Höhne, G. W. H. et al(1996), Differential Scanning calorimetry, Springer, Berlin.

The crystalline forms of compound (I) of the present invention may alsoexist as solvates, including hydrates.

The present invention also relates to the use of a crystalline form ofcompound (I), as hereinbefore defined.

A crystalline form of compound (I), as hereinbefore defined has one ormore advantageous properties. For example, in some embodiments, acrystalline form of compound (I) shows advantageous properties, such as,for example, a high melting point, a substantial lack of solvent (e.g.,water) content, little or no weight loss on heating, and/or lowhygroscopicity. In certain embodiments, such properties advantageouslyfacilitate the manufacture, storage, formulation, and/or delivery ofcompound (I).

A crystalline form of compound (I), as described herein, for exampleForm I of compound (I) provide advantageous properties with regard tostability.

A substance can be expected to be more stable chemically in acrystalline state in comparison with the same substance in an amorphousstate, as described in Haleblian and McCrone J. Pharm. Sci 1969, 58,pages 911-929, especially page 913. This observation is common for smallmolecules (i.e. non-proteins) but not always true for macromoleculeslike proteins, as described in Pikal and Rigsbee, Pharm. Res. 1997, 14,pages 1379-1387, especially page 1379. A crystalline state is thusbeneficial for small molecules such as compound (I).

X-rays will be scattered by electrons in atoms in a substance.Crystalline material will diffract X-rays giving peaks in directions ofconstructive interference. The directions are determined by the crystalstructure, including the size and shape of the unit cell. Alldiffraction peak °2Theta values disclosed and/or claimed herein refer toCu Kα-radiation. An amorphous (non-crystalline) material will not givesuch diffraction peaks. See e.g. Klug, H. P. & Alexander, L. E., X-RayDiffraction Procedures For Polycrystalline and Amorphous Materials,1974, John Wiley & Sons.

The ability for a compound to lump together or cake without control willincrease if the compound is heated to near its melting temperature.Lumps and cakes will have different flow and dissolution properties ascompared with a powder. Mechanical treatment of a powder, such as duringparticle size reduction, will bring energy into the material and thusgive a possibility to raise the temperature. Storage of a compound aswell as transport of a compound can unintentionally also lead to anincreased temperature. Melting is an endothermic event. Endothermicevents can be measured by, e.g. differential scanning calorimetry (DSC).

It is thus beneficial for a compound of formula (I) or apharmaceutically acceptable salt thereof salt thereof to have suchendothermic events at a temperature higher than the highest temperatureexpected during normal use to prevent said compounds from forming anundesired lump or cake.

Pharmaceutical Formulations

According to one aspect of the present invention there is provided apharmaceutical formulation comprising a crystalline form of the compound(I), such as Form I, for use in the prevention and/or treatment ofconditions associated with the H3 receptor.

The formulation used in accordance with the present invention may be ina form suitable for oral administration, for example such as a tablet,pill, powder, granule or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),for topical administration for example such as an ointment, patch orcream, for rectal administration for example such as a suppository andfor other non-parenteral administration.

Suitable daily doses a crystalline form of the compound (I), such asForm I, in the treatment of a mammal, including human, are approximately0.01 to 250 mg/kg bodyweight at per oral administration and about 0.001to 250 mg/kg bodyweight at parenteral administration. The typical dailydose of the active ingredients varies within a wide range and willdepend on various factors such as the relevant indication, the route ofadministration, the age, weight and sex of the patient and may bedetermined by a physician.

A crystalline form of compound (I), such as for example Form I, may beused on its own but will usually be administered in the form of apharmaceutical formulation in which the active ingredient is inassociation with pharmaceutically acceptable diluents, excipients and/orinert carrier known to a person skilled in the art. Dependent on themode of administration, the pharmaceutical formulation may comprise from0.05 to 99% w (percent by weight), for example from 0.10 to 50% w, ofactive ingredient, all percentages by weight being based on totalcomposition.

The invention further provides a process for the preparation of apharmaceutical formulation of the invention which comprises mixing of acrystalline form of the compound (I), such as form I, as hereinbeforedefined, with pharmaceutically acceptable diluents, excipients and/orinert carriers.

Medical Uses

In one embodiment, at least one crystalline form of the compound (I)described herein may be administered to a mammal, including human, to beused to modulate at least one histamine H3 receptor. The terms“modulate”, “modulates”, “modulating”, or “modulation”, as used herein,refer to, for example, the activation (e.g., agonist activity) orinhibition (e.g., antagonist and inverse agonist activity) of at leastone histamine H3 receptor. In one embodiment, at least one crystallineform of the compound (I) described herein may be administered to amammal, including human, to be used as an inverse agonist of at leastone histamine H3 receptor. In another embodiment, at least onecrystalline form of the compound (I) described herein may beadministered to a mammal, including human, to be used as an antagonistof at least one histamine H3 receptor. In another embodiment, at leastone crystalline form of the compound (I) described herein may be used asan antagonist of at least one histamine H3 receptor. In yet anotherembodiment, at least one crystalline form of the compound (I) describedherein may be used an antagonist of at least one histamine H3 receptor.

At least one crystalline form of the compound (I) described herein maybe administered to a mammal, including human, to be used to treat one ormore of a wide range of conditions or disorders in which modulating thehistamine H3 receptor is beneficial. At least one crystalline form ofthe compound (I) described herein may administered to a mammal,including human, to be, for example, be useful to treat at least onedisease of the central nervous system, the peripheral nervous system,the cardiovascular system, the pulmonary system, the gastrointestinalsystem, or the endocrinological system.

Another embodiment provides a method for treating a disorder in whichmodulating the function of at least one histamine H3 receptor isbeneficial comprising administering to a warm-blooded animal in need ofsuch treatment a therapeutically effective amount of crystalline form ofthe compound (I).

One embodiment relates to the use of the crystalline form of a compound(I) in the manufacture of a medicament for the treatment of at least onedisorder selected from schizophrenia, narcolepsy, excessive daytimesleepiness, obesity, attention deficit hyperactivity disorder, pain,neuropathic pain, Alzheimer's disease, cognition deficiency, andcognition deficiency associated with schizophrenia.

A further embodiment relates to a method for the therapy of at least onedisorder selected from schizophrenia, narcolepsy, excessive daytimesleepiness, obesity, attention deficit hyperactivity disorder, pain,neuropathic pain, Alzheimer's disease, cognition deficiency, andcognition deficiency associated with schizophrenia, in a warm-bloodedanimal in need of such therapy, wherein the method comprisesadministering to the animal a therapeutically effective amount of acrystalline form of the compound (I).

A crystalline form of the compound (I) may be useful to treat at leastone autoimmune disorder. Exemplary autoimmune disorders include, but arenot limited to, for example, arthritis, skin grafts, organ transplantsand similar surgical needs, collagen diseases, various allergies, tumorsand viruses.

A crystalline form of the compound (I) may be useful to treat at leastone psychiatric disorder.

Exemplary psychiatric disorders include, but are not limited to, forexample, Psychotic Disorder(s) and Schizophrenia Disorder(s), such as,for example, Schizoaffective Disorder(s), Delusional Disorder(s), BriefPsychotic Disorder(s), Shared Psychotic Disorder(s), and PsychoticDisorder(s) Due to a General Medical Condition; Dementia and otherCognitive Disorder(s); Anxiety Disorder(s), such as, for example, PanicDisorder(s) Without Agoraphobia, Panic Disorder(s) With Agoraphobia,Agoraphobia Without History of Panic Disorder(s), Specific Phobia,Social Phobia, Obsessive-Compulsive Disorder(s), Stress relatedDisorder(s), Posttraumatic Stress Disorder(s), Acute Stress Disorder(s),Generalized Anxiety Disorder(s) and Generalized Anxiety Disorder(s) Dueto a General Medical Condition; Mood Disorder(s), such as, for example,a) Depressive Disorder(s) (including but not limited to, for example,Major Depressive Disorder(s) including depression, major depression,mood stabilization and/or apathy, and Dysthymic Disorder(s)), b) BipolarDepression and/or Bipolar mania, such as, for example, Bipolar I (whichincludes, but is not limited to those with manic, depressive or mixedepisodes), Bipolar II, and Bipolar Maintenance, c) Cyclothymiac'sDisorder(s), and d) Mood Disorder(s) Due to a General Medical Condition;Sleep Disorder(s), such as, for example, excessive daytime sleepiness,narcolepsy, hypersomina, and sleep apnea; Disorder(s) Usually FirstDiagnosed in Infancy, Childhood, or Adolescence including, but notlimited to, for example, Mental Retardation, Down's Syndrome, LearningDisorder(s), Motor Skills Disorder(s), Communication Disorders(s),Pervasive Developmental Disorder(s), is Attention-Deficit and DisruptiveBehavior Disorder(s), Feeding and Eating Disorder(s) of Infancy or EarlyChildhood, Tic Disorder(s), and Elimination Disorder(s);Substance-Related Disorder(s) including, but not limited to, forexample, Substance Dependence, Substance Abuse, Substance Intoxication,Substance Withdrawal, Alcohol-Related Disorder(s), Amphetamines (orAmphetamine-Like)-Related Disorder(s), Caffeine-Related Disorder(s),Cannabis-Related Disorder(s), Cocaine-Related Disorder(s),Hallucinogen-Related Disorder(s), Inhalant-Related Disorder(s),Nicotine-Related Disorder(s), Opiod-Related Disorder(s), Phencyclidine(or Phencyclidine-Like)-Related Disorder(s), and Sedative-, Hypnotic- orAnxiolytic-Related Disorder(s); Attention-Deficit and DisruptiveBehavior Disorder(s); Eating Disorder(s), such as, for example, obesity;Personality Disorder(s) including, but not limited to, for example,Obsessive-Compulsive Personality Disorder(s); Impulse-ControlDisorder(s); Tic Disorders including, but not limited to, for exampleTourette's Disorder, Chronical Tics Syndrome, Chronic motor or vocal ticdisorder; and Transient Tic Disorder. At least one of the abovepsychiatric disorders is defined, for example, in the AmericanPsychiatric Association: Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition, Text Revision, Washington, D.C., AmericanPsychiatric Association, 2000.

A crystalline form of the compound (I) may be useful: i) to treatobesity or being overweight (e.g., promotion of weight loss andmaintenance of weight loss), eating disorders (e.g., binge eating,anorexia, bulimia and compulsive), and/or cravings (for drugs, tobacco,alcohol, any appetizing macronutrients or non-essential food items); ii)to prevent weight gain (e.g., medication-induced or subsequent tocessation of smoking); and/or iii) to modulate appetite and/or satiety.At least one solid form described herein may be suitable for treatingobesity by reducing appetite and body weight and/or maintaining weightreduction and preventing rebound. At least one solid form describedherein may be used to prevent or reverse medication-induced weight gain,e.g., weight gain caused by antipsychotic (neuroleptic) treatment(s);and/or weight gain associated with smoking cessation.

A crystalline form of the compound (I) may be useful to treat at leastone Neurodegenerative Disorder.

Exemplary Neurodegenerative Disorders include, but are not limited to,for example, conditions associated with cognitive disorder(s) orindications with deficit(s) in cognition is such as: dementia; incl.pre-senile dementia (early onset Alzheimer's Disease); senile dementia(dementia of the Alzheimer's type); Alzheimer's Disease (AD); FamilialAlzheimer's disease; Early Alzheimer's disease; mild to moderatedementia of the Alzheimer's type; delay of disease progression ofAlzheimer's Disease; neurodegeneration associated with Alzheimer'sdisease, Mild Cognitive Impairment (MCI); Amnestic Mild CognitiveImpairment (aMCI); Age-associated Memory Impairment (AAMI); Lewy bodydementia; vascular dementia (VD); HIV-dementia; AIDS dementia complex;AIDS—Neurological Complications; Frontotemporal dementia (FTD);Frontotemporal dementia Parkinson's Type (FTDP); dementia pugilistica;dementia due to infectious agents or metabolic disturbances; dementia ofdegenerative origin; dementia-Multi-Infarct; memory loss; cognition inParkinson's Disease; cognition in multiple sclerosis; cognition deficitsassociated with chemotherapy; Cognitive Deficit in Schizophrenia (CDS);Schizoaffective disorders including schizophrenia; Age-Related CognitiveDecline (ARCD); Cognitive Impairment No Dementia (CIND); CognitiveDeficit arising from stroke or brain ischemia; Congenital and/ordevelopment disorders; progressive supranuclear palsy (PSP); amyotrophiclateral sclerosis (ALS); corticobasal degeneration (CBD); traumaticbrain injury (TBI); postencephelatic parkinsonism; Pick's Disease;Niemann-Pick's Disease; Down's syndrome; Huntington's Disease;Creurtfeld-Jacob's disease; prion diseases; multiple sclerosis (MS);motor neuron diseases (MND); Parkinson's Disease (PD); β-amyloidangiopathy; cerebral amyloid angiopathy; Trinucleotide Repeat Disorders;Spinal Muscular Atrophy; Ataxia; Friedreich's Ataxia; Ataxias andCerebellar or Spinocerebellar Degerneration; Neuromyelitis Optica;Multiple System Atrophy; Transmissible Spongiform Encephalopathies;Attention Deficit Disorder (ADD); Attention Deficit HyperactivityDisorder (ADHD); Bipolar Disorder (BD) including acute mania, bipolardepression, bipolar maintenance; Major Depressive Disorders (MDD)including depression, major depression, mood disorder (stabilization),dysthymia and apathy; Guillain-Barré Syndrome (GBS); and ChronicInflammatory Demyelinating Polyneuropathy (CIDP).

A crystalline form of the compound (I) may be useful to treat at leastone Neuroinflammatory Disorder including, but not limited to, forexample, Multiple Sclerosis (MS), which includes, but is not limited to,for example, Relapse Remitting Multiple Sclerosis (RRMS), SecondaryProgressive Multiple Sclerosis (SPMS), and Primary Progressive MultipleSclerosis (PPMS); Parkinson's disease; Multiple System Atrophy is (MSA);Corticobasal Degeneration; Progressive Supranuclear Paresis;Guillain-Barré Syndrome (GBS); and chronic inflammatory demyelinatingpolyneuropathy (CIDP).

A crystalline form of the compound (I) may be useful to treat at leastone Attention-Deficit and Disruptive Behavior Disorder.

Exemplary Attention-Deficit and Disruptive Behavior Disorders include,but are not limited to, for example, attention deficit disorder (ADD),attention deficit hyperactivity disorder (ADHD), and affectivedisorders.

A crystalline form of the compound (I) may be useful to treat pain,including acute or chronic pain disorders including but not limited to,for example, Widespread pain, Localized pain, Nociceptive pain,Inflammatory pain, Central pain, Central and peripheral neuropathicpain, Diabetic neuropathic pain, Central and peripheral neurogenic pain,Central and peripheral neuralgia, Low back pain, Postoperative pain,Visceral pain, and Pelvic pain; Allodynia; Anesthesia dolorosa;Causalgia; Dysesthesia; Fibromyalgia; Hyperalgesia; Hyperesthesia;Hyperpathia; Ischemic pain; Sciatic pain; Burn-induced pain; Painassociated with cystitis including, but not limited to, interstitialcystitis; Pain associated with multiple sclerosis; Pain associated witharthritis; Pain associated with osteoarthritis; Pain associated withrheumatoid arthritis; Pain associated with pancreatitis; Pain associatedwith psoriasis; Pain associated with fibromyalgia; Pain associated withIBS; Pain associated with cancer; and Restless Legs Syndrome.

A crystalline form of the compound (I) may be useful to treat at leastone of the following disorders Autism, Dyslexia, Jetlag, Hyperkinesias,Dystonias, Rage outbursts, Muscular Dystrophy, Neurofibromatosis, SpinalCord Injury, Cerebral Palsy, Neurological Sequelae of Lupus andPost-Polio Syndrome.

A crystalline form of the compound (I) may be used for the manufactureof a medicament for the treatment of at least one autoimmune disorder,psychiatric disorder, obesity disorder, eating disorder, cravingdisorder, neurodegenerative disorder, neuroinflammatory disorder,Attention-Deficit and Disruptive Behaviour Disorder, and/or paindisorder described hereinabove.

A crystalline form of the compound (I) may be used for the treatment ofat least one disorder selected from cognitive deficits in schizophreniaand Alzheimer's disease. One embodiment of the invention relates to theprevention and/or treatment of Alzheimer's Disease, especially the usein symptomatic treatment of mild to moderate Alzheimer's Disease or inthe treatment of mild to moderate dementia of Alzheimer type.

Other embodiments of the invention relate to the prevention and/ortreatment of disorders selected from the group consisting of attentiondeficit disorder (ADD), attention deficit hyperactivity disorder (ADHD)and affective disorders, wherein the affective disorders are BipolarDisorder including acute mania, bipolar depression, bipolar maintenance,major depressive disorders (MDD) including depression, major depression,mood stabilization, schizoaffective disorders including schizophrenia,and dysthymia.

Another aspect provides a method for treating at least one autoimmunedisorder, psychiatric disorder, obesity disorder, eating disorder,craving disorder, neurodegenerative disorder, neuroinflammatorydisorder, attention-deficit and disruptive behaviour disorder, and/orpain disorder in a warm-blooded animal, comprising administering to saidanimal in need of such treatment a therapeutically effective amount of acrystalline form of the compound (I).

Yet another aspect provides a method for treating at least one disorderselected from cognitive deficits in schizophrenia, narcolepsy, excessivedaytime sleepiness, obesity, attention deficit hyperactivity disorder,pain, neuropathic pain, and Alzheimer's disease in a warm-bloodedanimal, comprising administering to said animal in need of suchtreatment a therapeutically effective amount of a crystalline form ofthe compound (I).

Yet another aspect provides a method for treating cognitive deficits inschizophrenia in a warm-blooded animal, comprising administering to saidanimal in need of such treatment a to therapeutically effective amountof a crystalline form of the compound (I).

Yet another aspect provides a method for treating obesity in awarm-blooded animal, comprising administering to said animal in need ofsuch treatment a therapeutically effective amount of a crystalline formof the compound (I).

Yet another aspect provides a method for treating narcolepsy in awarm-blooded animal, comprising administering to said animal in need ofsuch treatment a therapeutically effective amount of a crystalline formof the compound (I).

Yet another aspect provides a method for treating excessive daytimesleepiness in a warm-blooded animal, comprising administering to saidanimal in need of such treatment a therapeutically effective amount of acrystalline form of the compound (I).

One embodiment of the invention relates to the prevention and/ortreatment of Alzheimer's Disease, especially the use in the delay of thedisease progression of Alzheimer's Disease.

Other embodiments of the invention relate to the prevention and/ortreatment of disorders selected from the group consisting of attentiondeficit disorder (ADD), attention deficit hyperactivity disorder (ADHD)and affective disorders, wherein the affective disorders are BipolarDisorder including acute mania, bipolar depression, bipolar maintenance,major depressive disorders (MDD) including depression, major depression,mood stabilization, schizoaffective disorders including schizophrenia,and dysthymia.

Still another aspect provides a method for treating Alzheimer's diseasein a warm-blooded animal, comprising administering to said animal inneed of such treatment a therapeutically effective amount of acrystalline form of the compound (I).

Still yet another aspect provides a method for treating attentiondeficit hyperactivity disorder in a warm-blooded animal, comprisingadministering to said animal in need of such treatment a therapeuticallyeffective amount of a crystalline form of the compound (I).

Yet still another aspect provides a method for treating a pain disorderin a warm-blooded animal, comprising administering to said animal inneed of such treatment a therapeutically effective amount of acrystalline form of the compound (I).

Yet still another aspect provides a method for treating neuropathic painin a warm-blooded is animal, comprising administering to said animal inneed of such treatment a therapeutically effective amount of acrystalline form of the compound (I).

In one embodiment, the warm-blooded animal is a mammalian speciesincluding, but not limited to, for example, humans and domestic animals,such as, for example, dogs, cats, and horses. In one embodiment, thewarm-blooded animal is a human.

Another aspect provides the use of a crystalline form of the compound(I) in therapy.

Another embodiment provides the use of a crystalline form of thecompound (I) in the manufacture of a medicament for use in therapy.

Another aspect of the invention is wherein a compound of formula (I) asdefined herein, or a pharmaceutical composition or formulationcomprising a combination comprising such a compound of formula (I) isadministered, concurrently, simultaneously, sequentially, separately oradjunct with another pharmaceutically active compound or compoundsselected from the following:

-   -   (i) antidepressants including for example agomelatine,        amitriptyline, amoxapine, bupropion, citalopram, clomipramine,        desipramine, doxepin duloxetine, elzasonan, escitalopram,        fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone,        maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine,        protriptyline, ramelteon, reboxetine, robalzotan, sertraline,        sibutramine, thionisoxetine, tranylcypromaine, trazodone,        trimipramine, venlafaxine and equivalents and pharmaceutically        active isomer(s) and metabolite(s) thereof;    -   (ii) atypical antipsychotics including for example quetiapine        and pharmaceutically active isomer(s) and metabolite(s) thereof;    -   (iii) antipsychotics including for example amisulpride,        aripiprazole, asenapine, benzisoxidil, bifeprunox,        carbamazepine, clozapine, chlorpromazine, debenzapine,        divalproex, duloxetine, eszopiclone, haloperidol, iloperidone,        lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone,        perlapine, perphenazine, phenothiazine, phenylbutylpiperidine,        pimozide, prochlorperazine, risperidone, sertindole, sulpiride,        suproclone, suriclone, thioridazine, trifluoperazine,        trimetozine, valproate, valproic acid, zopiclone, zotepine,        ziprasidone and equivalents and pharmaceutically active        isomer(s) and is metabolite(s) thereof;    -   (iv) anxiolytics including for example alnespirone, azapirones,        benzodiazepines, barbiturates such as adinazolam, alprazolam,        balezepam, bentazepam, bromazepam, brotizolam, buspirone,        clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam,        diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam,        fosazepam, lorazepam, lormetazepam, meprobamate, midazolam,        nitrazepam, oxazepam, prazepam, quazepam, reclazepam,        tracazolate, trepipam, temazepam, triazolam, uldazepam,        zolazepam and equivalents and pharmaceutically active isomer(s)        and metabolite(s) thereof;    -   (v) anticonvulsants including for example carbamazepine,        clonazepam, ethosuximide, felbamate, fosphenyloin, gabapentin,        lacosamide, lamotrogine, levetiracetam, oxcarbazepine,        phenobarbital, phenyloin, pregabaline, rufinamide, topiramate,        valproate, vigabatrine, zonisamide, and equivalents and        pharmaceutically active isomer(s) and metabolite(s) thereof;    -   (vi) Alzheimer's therapies including for example donepezil,        rivastigmine, galantamine, memantine, and equivalents and        pharmaceutically active isomer(s) and metabolite(s) thereof;    -   (vii) Parkinson's therapies including for example levodopa,        dopamine agonists such as apomorphine, bromocriptine,        cabergoline, pramipexol, ropinirole, and rotigotine, MAO-B        inhibitors such as selegeline and rasagiline, and other        dopaminergics such as tolcapone and entacapone, A-2 inhibitors,        dopamine reuptake inhibitors, NMDA antagonists, Nicotine        agonists, and inhibitors of neuronal nitric oxide synthase and        equivalents and pharmaceutically active isomer(s) and        metabolite(s) thereof;    -   (viii) migraine therapies including for example almotriptan,        amantadine, bromocriptine, butalbital, cabergoline,        dichloralphenazone, dihydroergotamine, eletriptan, frovatriptan,        lisuride, naratriptan, pergolide, pizotiphen, pramipexole,        rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan,        and equivalents and pharmaceutically active isomer(s) and        metabolite(s) thereof;    -   (ix) stroke therapies including for example thrombolytic therapy        with eg activase and desmoteplase, abciximab, citicoline,        clopidogrel, eptifibatide, minocycline, and equivalents and        pharmaceutically active isomer(s) and metabolite(s) thereof;    -   (x) urinary incontinence therapies including for example        darafenacin, falvoxate, oxybutynin, propiverine, robalzotan,        solifenacin, tolterodine and equivalents and pharmaceutically        active isomer(s) and metabolite(s) thereof;    -   (xi) neuropathic pain therapies including lidocain, capsaicin,        and anticonvulsants is such as gabapentin, pregabalin, and        antidepressants such as duloxetine, venlafaxine, amitriptyline,        klomipramine, and equivalents and pharmaceutically active        isomer(s) and metabolite(s) thereof;    -   (xii) nociceptive pain therapies including paracetamol, NSAIDS        and coxibs, such as celecoxib, etoricoxib, lumiracoxib,        valdecoxib, parecoxib, diclofenac, loxoprofen, naproxen,        ketoprofen, ibuprofen, nabumeton, meloxicam, piroxicam and        opioids such as morphine, oxycodone, buprenorfin, tramadol and        equivalents and pharmaceutically active isomer(s) and        metabolite(s) thereof;    -   (xiii) insomnia therapies including for example agomelatine,        allobarbital, alonimid, amobarbital, benzoctamine, butabarbital,        capuride, chloral, cloperidone, clorethate, dexclamol,        ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine,        mecloqualone, melatonin, mephobarbital, methaqualone, midaflur,        nisobamate, pentobarbital, phenobarbital, propofol, ramelteon,        roletamide, triclofos, secobarbital, zaleplon, zolpidem and        equivalents and pharmaceutically active isomer(s) and        metabolite(s) thereof;    -   (xiv) mood stabilizers including for example carbamazepine,        divalproex, gabapentin, lamotrigine, lithium, olanzapine,        quetiapine, valproate, valproic acid, verapamil, and equivalents        and pharmaceutically active isomer(s) and metabolite(s) thereof;    -   (xv) obesity therapies, such as, for example, anti-obesity drugs        that affect energy expenditure, glycolysis, gluconeogenesis,        glucogenolysis, lipolysis, lipogenesis, fat absorption, fat        storage, fat excretion, hunger and/or satiety and/or craving        mechanisms, appetite/motivation, food intake, and G-I motility;        very low calorie diets (VLCD); and low-calorie diets (LCD);    -   (xvi) therapeutic agents useful in treating obesity associated        disorders, such as, for example, biguanide drugs, insulin        (synthetic insulin analogues) and oral antihyperglycemics (these        are divided into prandial glucose regulators and        alpha-glucosidase inhibitors), PPAR modulating agents, such as,        for example, PPAR alpha and/or gamma agonists; sulfonylureas;        cholesterol-lowering agents, such as, for example, inhibitors of        HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A        reductase); an inhibitor of the ileal bile acid transport system        (IBAT inhibitor); a bile acid binding resin; bile acid        sequestering agent, such as, for example, colestipol,        cholestyramine, or cholestagel; a CETP (cholesterol ester        transfer protein) inhibitor; a cholesterol absorption is        antagonist; a MTP (microsomal transfer protein) inhibitor; a        nicotinic acid derivative, including slow release and        combination products; a phytosterol compound; probucol; an        anti-coagulant; an omega-3 fatty acid; an anti-obesity therapy,        such as, for example, sibutramine, phentermine, orlistat,        bupropion, ephedrine, and thyroxine; an antihypertensive, such        as, for example, an angiotensin converting enzyme (ACE)        inhibitor, an angiotensin II receptor antagonist, an adrenergic        blocker, an alpha adrenergic blocker, a beta adrenergic blocker,        a mixed alpha/beta adrenergic blocker, an adrenergic stimulant,        calcium channel blocker, an AT-1 blocker, a saluretic, a        diuretic, and a vasodilator; a melanin concentrating hormone        (MCH) modulator; an NPY receptor modulator; an orexin receptor        modulator; a phosphoinositide-dependent protein kinase (PDK)        modulator; modulators of nuclear receptors, such as, for        example, LXR, FXR, RXR, GR, ERRα, β, PPARα, β, γ and RORalpha; a        monoamine transmission-modulating agent, such as, for example, a        selective serotonin reuptake inhibitor (SSRI), a noradrenaline        reuptake inhibitor (NARI), a noradrenaline-serotonin reuptake        inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a        tricyclic antidepressive agent (TCA), a noradrenergic and        specific serotonergic antidepressant (NaS SA); a serotonin        receptor modulator; a leptin/leptin receptor modulator; a        ghrelin/ghrelin receptor modulator; a DPP-IV inhibitor; and        equivalents and pharmaceutically active isomer(s),        metabolite(s), and pharamaceutically acceptable salts, solvates,        and prodrugs thereof;    -   (xvii) agents for treating ADHD, such as, for example,        amphetamine, methamphetamine, dextroamphetamine, atomoxetine,        methylphenidate, dexmethylphenidate, modafinil, and equivalents        and pharmaceutically active isomer(s) and metabolite(s) thereof;        and    -   (xviii) agents used to treat substance abuse disorders,        dependence, and withdrawal, such as, for example, nicotine        replacement therapies (i.e., gum, patches, and nasal spray);        nicotinergic receptor agonists, partial agonists, and        antagonists, (e.g., varenicline); acomprosate, bupropion,        clonidine, disulfuram, methadone, naloxone, naltrexone, and        equivalents and pharmaceutically active isomer(s) and        metabolite(s) thereof.

The dose required for the therapeutic or preventive treatment of aparticular disease will necessarily be varied depending on the hosttreated, the route of administration and the severity of the illnessbeing treated.

For veterinary use the amounts of different components, the dosage formand the dose of the medicament may vary and will depend on variousfactors such as, for example the individual requirement of the animaltreated.

When employed in combination with at least one solid form describedherein, the above other pharmaceutically active compound may be used,for example, in the amounts indicated in the Physicians' Desk Reference(PDR; e.g., 64th ed. 2010) or approved dosage ranges and/or dosagedescribed in published references or as otherwise determined by one ofordinary skill in the art.

Dosages can be readily ascertained by those skilled in the art based onthis disclosure and the knowledge in the art. Thus, the skilled personcan readily determine the amount of crystalline form and optionaladditives, vehicles, and/or carriers in compositions and to beadministered in methods provided herein. The specific dose level andfrequency of dosage for any particular subject, however, may vary andgenerally depends on a variety of factors, including, but not limitedto, for example, the dissolution and/or bioavailability of the solidform(s) described herein; species, age, body weight, general health,sex, and diet of the subject; mode and time of administration; rate ofexcretion; drug combination; and severity of the particular condition.

In the context of the present specification, the term “therapy” alsoincludes “prevention” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

In the context of the present specification, the term “disorder” alsoincludes “condition” unless there are specific indications to thecontrary.

In one embodiment of the invention the combination comprises the groupof compounds

(a) and (b) as defined below:

(a) a first therapeutic agent, which is a H3 inhibitor and (b) a secondtherapeutic agent, which is a NMDA-receptor antagonist selected from:

(a) a first therapeutic agent, which is a crystalline form of compound(I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,such as for example Form I, and (b) a second therapeutic agent, which ismemantine;

(a) a first therapeutic agent, which is a H3 antagonist or inverseagonist and (b) a second therapeutic agent, which is a acetyl cholineesteras inhibitor.

(a) a first therapeutic agent, which is a crystalline form of compound(I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,such as for example Form I, and (b) a second therapeutic agent, which isa donepezil.

(a) a first therapeutic agent, which is a crystalline form of compound(I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,such as for example Form I, and (b) a second therapeutic agent, which isa rivastigmine.

(a) a first therapeutic agent, which is a crystalline form of compound(I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,such as for example Form I, and (b) a second therapeutic agent, which isa galantamine.

(a) a first therapeutic agent, which is a H3 inhibitor and (b) a secondtherapeutic agent, which is a voltage-gated calcium channel inhibitorselected from:

(a) a first therapeutic agent, which is a crystalline form of compound(I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,such as for example Form I, and (b) a second therapeutic agent, which ispregabalin.

(a) a first therapeutic agent, which is a crystalline form of compound(I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,such as for example Form I, and (b) a second therapeutic agent, which isgabapentin.

Such combination products employ the compound of this invention withinthe dosage range described herein and the other pharmaceutically activecompound or compounds within approved dosage ranges and/or the dosagedescribed in the publication reference.

Methods of Preparation

A process for the preparation of a crystalline form of a compound (I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,Form I, are described in comprising the following steps:

-   -   a) dissolving (1s,        25)-2-(4-Carbamoyl-phenyl)-cyclopropanecarboxylic acid and        cyclobutylpiperazine or a suitable salt thereof (for example the        dihydrochloride) in is a suitable solvent such as DMSO in the        presence of a base such as N-methylmorpholine;    -   b) adding an activating agent such as a mixture of        1-hydroxybenzotriazole/N-methylmorpholine and        1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in a        suitable solvent such as DMSO; followed by    -   c) heating the solution to 60° C. and adjusting pH to about 8        with a base such as an trialkylamine for example triethylamine;        followed by    -   d) cooling to 20° C., adding water and let to stirring for 16        hr.; followed by    -   e) filtering off the product; followed by    -   f) slurry washing with cold water; followed by    -   g) drying the obtained solid under vacuum at 40° C. to obtain a        crystalline Form I of compound (I).

Alternatively, the compound of formula (I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,dissolved or as a slurry of amorphous material, may be crystallised in asuitable solvent, such as, for example dimethylsulfoxide (DMSO), wateror mixtures thereof. Other suitable solvents for crystallisation arelower alcohols, such as, for example, methanol, ethanol, 1-propanol,2-propanol. 1-butanol and water or mixtures thereof.

Crystallization of the compound of formula (I) from an appropriatesolvent system, containing at least one solvent, may be achieved byattaining supersaturation in a solvent system by solvent evaporation, bytemperature decrease, and/or via the addition of antisolvent (i.e. asolvent in which the compounds of the invention are poorly soluble)and/or by a chemical reaction. An example of a suitable solvent is DMSOand an example of a suitable antisolvent is water.

Crystallisation temperatures and times depend upon the concentration inthe solution and the solvent system used.

Crystallisation may also be initiated and/or effected by way of standardtechniques, for example with or without seeding with crystals of theappropriate crystalline compound of the invention.

The crystalline form of a compounds of formula (I) may be isolated usingtechniques, which are well known to those skilled in the art, forexample decanting, filtering or centrifuging.

The crystalline form of a compounds of formula (I) may be dried usingstandard is techniques, which are well known to those skilled in theart.

Alternatively, a crystalline form of compound of formula (I) may befurther purified by column chromatography on silica eluting with asuitable organic solvent or a mixture of solvents, such as for examplemixtures of dichloromethane and methanol optionally containing ammoniain methanol.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an X-ray powder diffractogram (XRDP) pattern for Form I ofCompound (I).

FIG. 2 shows a differential scanning calorimetry (DSC) thermogram forForm I of Compound (I).

WORKING EXAMPLES

The invention is further defined in the following Examples. It should beunderstood that the Examples are given by way of illustration only. Fromthe above discussion and the Examples, one skilled in the art canascertain the essential characteristics of the invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications to adapt the invention to various uses and conditions.As a result, the invention is not limited by the illustrative examplesset forth herein below, but rather defined by the claims appendedhereto.

All temperatures are in degrees Celsius (° C.) and are uncorrected.Unless otherwise noted, commercial reagents used in preparing theexample compounds were used as received without additional purification.

Unless otherwise noted, the solvents used in preparing the examplecompounds were commercial anhydrous grades and were used without furtherdrying or purification. Compounds used as starting materials in theExample and Methods are commercially available otherwise a process forpreparing them are described in the Intermediates A-F herein.

Example 14-{(1S,2S)-2-[(4-Cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,Form I

First Method

Intermediate E (5.52 g, 26.7 mmoles, 99.1% w/w) and Intermediate F (6.07g, 28.0 mmoles, 98.40% w/w) were mixed in DMSO (82 mL) at t_(jacket)=22°C. N-Methylmorpholine (2.94 mL, 27.2 mmoles) was added over 5 min. Thecharging vessel was rinsed with DMSO (2.8 mL). HOBt/NMM solution (1.80g, 2.66 mmoles, 20% w/w) was added in one portion. The charging vesselwas rinsed with DMSO (2.8 mL). EDCI×HCl (7.16 g, 38.0 mmoles) was addedover 10 min. at t_(jacket)=22° C. The reaction was complete after 2 h.The reaction solution was then heated to 60° C. and pH adjusted with TEA(5.18 g g, 51.2 mmol) to pH-8. The solid mixture was cooled to 20° C.after which H₂O (69.8 mL) was added and left to stir for 16 h. Theproduct was filtered off, and slurry washed with cold H₂O (2×33 mL).Drying under vacuum at 40° C. gave 7.53 g (22.8 mmoles, 99.0% w/w), 85%yield. ¹H-NMR (DMSO-d₆): δ 7.91 (br s, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.29(br s, 1H), 7.24 (d, J=8.0 Hz, 2H), 3.68-3.39 (m, 4H), 2.72-2.62 (m,1H), 2.40-2.29 (m, 2H), 2.26-2.12 (m, 4H), 1.99-1.88 (m, 2H), 1.83-1.70(m, 2H), 1.67-1.56 (m, 2H), 1.47-1.39 (m, 1H), 1.28-1.20 (m, 1H); LC-MS(ESI): m/z 328 (M+1). The chiral purity of the product was analyzed on achiral column with UV-detection (250 nm) using isocratic method (mobilephase: Heptane/EtOH (80/20)+0.1% Diethylamine) on Chiralpak AD-H,4.6×150 mm, giving an enantiomeric purity of >99% ee.

Second Method

4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide(10 gram, 30.54 mmoles) was dissolved in DMSO (83 ml) at 70° C. andscreened filtered into a reactor. The filter was rinsed with DMSO (17ml) into the reactor. The temperature was decreased to 55° C. and seedcrystals of4-{(1S,25)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamidewere added (0.2 gram, 0.61 moles). Then after 30 is minutes the slurrywas cooled to 20° C. over 3.5 hrs. At 20° C., water (40 ml) was chargedover 2.5 hrs. After charging the slurry remained at 20° C. foradditional 12 hrs. before isolation. The solid product was washed(displacement wash) with a mixture of DMSO (28 ml) and water (12 ml)followed by three water (3×40 ml), one slurry wash and two displacementwashes. Then the solid product was dried for 18 hrs. at 60° C. to obtainthe title compound in 9.32 gram (28.5 mmoles), 93% yield as crystals.

Third Method

4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide(3.0 gram, 9.16 mmoles) was dissolved in methanol (34.5 ml) and water(6.0 ml) at 65° C. and screened filtered into a reactor. Then thetemperature was decreased to 55° C. and followed by addition of seedcrystals of4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide(0.06 gram, 0.18 mmoles). After 5 minutes the slurry was cooled to 20°C. over 3.5 hrs. At 20° C., water (31.5 ml) was charged over 3.5 hrs.Then after additional 2 hrs, the solid form was isolated and washedtwice with a mixture of methanol (9 ml) and water (3 ml). Finally, thesolid product was dried at 60° C. for 15 hrs to obtain the titlecompound in 2.49 gram. (7.60 mmoles), 81% yield as crystals.

The solid product obtained in the first method was analysed by XRPD. Arepresentative XRPD pattern is shown in FIG. 1. Selected peaks areprovided in Table 1. The XRPD pattern confirmed the solid material to beCrystalline Form I.

TABLE 1 Selected XRPD peaks of Crystalline Form I Measured AngleRelative Peak [°2Th.] intensity 1 4.9 s 2 5.3 m 3 9.0 w 4 12.6 w 5 16.4m 6 16.6 m 7 18.3 vs 8 19.6 s 9 20.4 s 10 21.2 m 11 23.2 m 12 24.6 w

The solid product obtained in the second and third method, respectively,were analysed by XRPD and a representative XRPD pattern as shown in FIG.1 and with selected peaks as are provided in Table 1 were obtained. TheXRPD pattern confirmed the solid material to be Crystalline Form I.

to Solid product obtained according to method 1 of the Example 1 wasanalyzed by thermal techniques. DSC analysis indicated that Form I ofCompound (I) is a high melting solid. The DSC-trace shows a smallendothermic event, onset at 225° C., followed by a distinct endothermicevent, onset at 235° C. A representative DSC thermogram is shown in FIG.2.

X-Ray Powder Diffraction Analysis

An XRDP pattern for Crystalline Form I was collected using an XRPDinstrumentation as described below.

An X-Ray Powder Diffraction (XRPD) pattern was collected under ambientconditions on a PANalytical X'Pert PRO MPD theta-theta system usinglong-fine-focus Cu Kα-radiation, wavelength of X-rays 1.5418 Å, at 45 kVand 40 mA. A programmable divergence slit and a programmableanti-scatter slit giving an irradiated length of 10 mm were used. 0.02radian Soller slits were used on the incident and on the diffracted beampath. A 20 mm fixed mask was used on the incident beam path and aNickel-filter was placed in front of a PIXcel-detector using 255 activechannels. A thin flat sample was prepared on a flat zero backgroundplate made of silicon using a spatula. The plate was mounted in a sampleholder and rotated in a horizontal position during measurement. Adiffraction pattern was collected between 2°2theta and 40°2theta in acontinuous scan mode. Total time for the scan was approximately 10minutes.

It is known in the art that an X-ray powder diffraction pattern may beobtained which has one or more measurement errors depending onmeasurement conditions (such as is equipment, sample preparation ormachine used). In particular, it is generally known that intensities inan X-ray powder diffraction pattern may fluctuate depending onmeasurement conditions and sample preparation. For example, personsskilled in the art of X-ray powder diffraction will realize that therelative intensities of peaks may vary according to the orientation ofthe sample under test and on the type and setting of the instrumentused. The skilled person will also realize that the position ofreflections can be affected by the precise height at which the samplesits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample may also have asmall effect. Hence a person skilled in the art will appreciate that thediffraction pattern data presented herein is not to be construed asabsolute and any crystalline form that provides a power diffractionpattern substantially identical to those disclosed herein fall withinthe scope of the present disclosure (for further information seeJenkins, R & Snyder, R. L. ‘Introduction to X-Ray Powder Diffractometry’John Wiley & Sons, 1996).

When herein reference is made to a compound according to the inventionbeing crystalline, suitably the degree of crystallinity as determined byX-ray powder diffraction data, is for example greater than about 10%, isfor example greater than about 20%, is for example greater than about30%, is for example greater than about 40%, is for example greater thanabout 50%, is for example greater than about 60%, such as greater thanabout 80%, particularly greater than about 90%, more particularlygreater than about 95%. In embodiments of the invention, the degree ofcrystallinity as determined by X-ray powder diffraction data is greaterthan about 98%, wherein the % crystallinity refers to the % by weight ofthe total sample mass which is crystalline.

Peak search on XRDP data of Crystalline Form I.

A manual peak search was done preceded by an angle correction againstNIST SRM 676 alumina (α-Al₂O₃) standard.

The measured relative intensities vs. the strongest peak are given asvery strong (vs) above 50%, as strong (s) between 25 and 50%, as medium(m) between 10 and 25% and as weak (w) between 5 and 10% relative peakheight.

Differential Scanning Calorimetry (DSC) Analysis

DSC from 25° C. to 350° C. was performed under nitrogen in an aluminumsample cup with a perforated lid using a NETZSCH DSC 204 instrument. Thescan rate was 10° C. per is minute. The sample size was less than 1 mg.It is well known that the DSC onset and peak temperatures as well asenergy values may vary due to, for example, the purity of the sample andsample size and due to instrumental parameters, especially thetemperature scan rate. Hence the DSC data presented are not to be takenas absolute values. A person skilled in the art can set up instrumentalparameters for a Differential scanning calorimeter so that datacomparable to the data presented here can be collected according tostandard methods, for example those described in Höhne, G. W. H. et al(1996), Differential Scanning calorimetry, Springer, Berlin.

Synthesis of Intermediates Intermediate A(R)-1-(4-Bromo-phenyl)-2-chloro-ethanol

Borane dimethylsulfide (2.0 kg, 24.8 moles, 94% w/w) was mixed intoluene (8 L) at t_(jacket)=20° C. (R)-(+)-Methyl-CBS-oxazaborolidine(2.6 kg, 2.74 moles, 1M) as a toluene solution was added. The chargingvessel was rinsed with toluene (0.5 L) and t_(jacket) was set to 45° C.1-(4-Bromo-phenyl)-2-chloro-ethanone (7.84 kg, 33.6 moles), which iscommercially available from Jiangyan Keyan Fine Chemical Co. Ltd, wasdissolved in 2-MeTHF (75 L) in a separate vessel and when t_(inner) wasabove 40° C. in the first vessel, the 2-MeTHF solution was added during3 h. The latter vessel was rinsed with 2-MeTHF (2 L) and added to thereaction mixture, which was left stirring at t_(jacket)=45° C. for 1 h.At full conversion, the reaction mixture was cooled to t_(jacket)=10° C.before slow quench with MeOH (36 L). The first litre of MeOH was addedduring 30 min. and the rest during additional 30 min. MeOH was distilledoff under vacuum at t_(jacket)=50° C. The organic solution left wascooled to t_(jacket)=20° C., washed with 1M HCl in H₂O (7 L conc HCl+73L H₂O) and concentrated under vacuum at t_(jacket)=50° C. toapproximately 40 L. Intermediate A obtained in a 2-MeTHF solution can bestored at 10° C. for 20 h or used directly in the next synthetic step.

Intermediate B (R)-2-(4-Bromo-phenyl)-oxirane

Aliquat® 175 (methyl tributyl ammonium chloride) (1.12 kg, 4.75 moles)was added to Intermediate A as a 2-MeTHF solution (33.6 moles, 40 L) att_(jacket)=20° C. NaOH (5.1 kg, 57.4 moles, 45% w/w) diluted in H₂O (2L) was added during 20 min. The reaction mixture was left stirring att_(jacket)=20° C. for 2 h. At full conversion the aq. phase wasseparated off and the organic phase washed with H₂O (2×25 L). 2-MeTHF(25 L) was added and the organic phase concentrated under vacuum att_(jacket)=50° C. to approximately 30 L. Intermediate B obtained in a2-MeTHF solution, can be stored at 5° C. for 140 h or used directly inthe next synthetic step.

Intermediate C (1S,2S)-2-(4-Bromo-phenyl)-cyclopropanecarboxylic acid

Triethyl phosphonoacetate (10.5 L, 51.9 moles, 98% w/w) was dissolved in2-MeTHF (14 L) at t_(jacket)=−20° C. Hexyl lithium in hexane (21 L, 48.3moles, 2.3 M) was added at a rate to maintain t_(inner) below 0° C. Thecharging vessel was rinsed with 2-MeTHF (3 L) and the reaction solutionwas left stirring at t_(jacket)=10° C. Intermediate B as a 2-MeTHFsolution (33.6 moles, 30 L) was added during 20 min. The charging vesselwas rinsed with 2-s MeTHF (2 L) and the reaction solution was leftstirring at t_(jacket)=65° C. for at least 16 h with the last 3 h att_(jacket)=75° C. At full conversion the reaction solution was cooled tot_(jacket)=20° C. NaOH (7.6 kg, 85.5 moles, 45% w/w) diluted in H₂O (12L) was added over 20 min. The reaction solution obtained was leftstirring at t_(jacket)=60° C. for at least 2 h. At full conversion thereaction solution was cooled to t_(jacket) ⁼²⁰° C., the aq. phase wasseparated off and the organic phase was extracted with H₂O (37 L). Thecombined aq. phases were acidified to pH<3.5 with H₃PO₄ (9 L, 131 moles,85% w/w) diluted in H₂O (12.5 L). Only 17 L of the diluted H₃PO_(4(aq))was used to achieve the pH<3.5. The acidic aq. phase was extracted with2-MeTHF (2×15 L). The combined organic phases including rinsing with2-MeTHF (2 L) were concentrated under vacuum at t_(jacket)=50° C. toapproximately 11 L. is The 2-MeTHF solution was diluted with EtOH (14.5L) at t_(jacket)=35° C. and H₂O (16 L) was added over 20 min. Thereaction solution was cooled to t_(jacket)=28° C. Seed (16 g, 0.066moles) was added and the solution was stirred for 2 h at t_(jacket)=28°C. The reaction mixture was cooled to t_(jacket) ⁼⁰° C. over 6 h andleft stirring for at least 1 h. Additional H₂O (8 L) was added during 40min. and the product was filtered off and washed with cold H₂O (10 L).Drying under vacuum at 40° C. gave 6.18 kg Intermediate C (21.5 moles,84% w/w), 64% yield over four steps from 7.84 kg1-(4-bromo-phenyl)-2-chloro-ethanone (33.6 moles).

Recrystallization of Intermediate C: Two batches of Intermediate C(6.18+7.04 kg) were mixed in EtOH (52 L) and heated at t_(jacket)=70° C.H₂O (52 L) was added. The reaction solution was cooled to t_(jacket)=30°C. over 2.5 h. H₂O (16 L) was added during 20 min. and thecrystallization was cooled to t_(jacket)=20° C. during 3 h. The productwas filtered off and washed with a mixture of H₂O (8 L) and EtOH (2 L).Drying under vacuum at 40° C. gave 10.0 kg Intermediate (41.5 moles, 88%w/w), which was redissolved in toluene (39 L) and isooctane (57 L) att_(jacket)=60° C. A clear solution was obtained. The reaction solutionwas cooled to t_(jacket)=45° C. and left stirring for 1 h, then cooledto t_(jacket)=20° C. over 2 h. The product was filtered off and washedwith a mixture of toluene (4 L) and isooctane (36 L) in two portions.Drying under vacuum at 40° C. gave 7.4 kg Intermediate C (29.8 moles,97% w/w), 44% yield over four steps from 7.84+7.93 kg1-(4-bromo-phenyl)-2-chloro-ethanone (67.5 moles). ¹H-NMR (DMSO-d₆): δ12.36 (s, 1H), 7.44 (d, 2H, J=8 Hz), 7.13 (d, 2H, J=8 Hz), 2.39 (m, 1H),1.81 (m, 1H), 1.43 (m, 1H), 1.33 (m, 1H); ¹³C-NMR (DMSO-d₆): δ 173.76,139.88, 131.20, 128.24, 119.14, 24.73, 24.31, 16.78; LC-MS (ESI): m/z239 (M−1 (Br⁷⁹)) and 241 (M−1 (Br⁸¹)).

Intermediate D (1S,2S)-2-(4-Cyano-phenyl)-cyclopropanecarboxylic acid

Intermediate C (3.7 kg, 14.9 moles, 97% w/w) and zinc-dust (98%+, <10μm) (99 g, 1.51 moles) were mixed with DMF (13.5 L) and the slurry wasstirred at t_(jacket)=20° C. The mixture was inerted and left with N₂pressure of 0.1-0.2 bar. Bis(tri-t-butylphosphine)palladium (0) (27.5 g,0.054 moles) was added to the slurry, and the vessel was inerted andleft with N₂ pressure of 0.1-0.2 bar. The mixture was heated tot_(jacket)=45° C., Zn (CN)₂ (1.0 kg, 8.52 moles) was added to thesuspension in one portion, and the system was inerted and left with N₂pressure of 0.1-0.2 bar (N. B. Cyanide salts are highly toxic). Theresulting mixture was heated to t_(jacket)=75° C. and stirred for atleast 2 h. At full is conversion the reaction mixture was cooled tot_(jacket)=20° C. Thiol-functionalized silica (Silicycle, SiliaBondThiol) (1.07 kg, 28% w/w) was added and the vessel was inerted. Thereaction mixture was stirred for at least 36 h at t_(jacket)=20° C. Thescavenger was filtered off via a filter with activated charcoal orequivalent (pall-filter). The vessel and the filter system were washedwith 2-MeTHF (53 L). The filtrate and washings were combined and stirredat t_(jacket)=5° C. A pale yellow liquid resulted. NaCl (3.5 kg) in H₂O(16.4 L) was added during 15 min. at such a rate so the innertemperature remained below 15° C. The resulting reaction mixture washeated to t_(jacket)=45° C. and the aq. phase was separated off. Theorganic phase was washed with NaHSO₄×H₂O in H₂O (2×(2.87 kg+16.4 L)) andNaCl in H₂O (3.5 kg+16.4 L). The organic phase was cooled tot_(jacket)=10° C. and NaOH (1.54 kg, 19.3 moles, 50% w/w) diluted in H₂O(41 L) was added during 45 min. The resulting reaction mixture washeated to t_(jacket)=30° C. and the organic phase separated off. The aq.phase was stirred at t_(jacket)=20° C. and pH adjusted to 6.5 with H₃PO₄(0.90 kg, 7.81 moles, 85% w/w) diluted in H₂O (5.3 L) at a rate thatmaintained the inner temperature below 25° C. 2-MeTHF and H₂O weredistilled off under vacuum until a volume 85-90% of the volume prior todistillation, approximately 8 L. The reaction mixture was cooled tot_(jacket)=0° C. and continued charging off H₃PO₄ (1.17 kg, 10.1 moles,85% w/w) diluted in H₂O (8.2 L) until pH=4. The slurry was left stirringovernight at t_(jacket)=10° C. The product was filtered off, washed withH₂O (2×4 L). Drying under vacuum at 40° C. gave Intermediate D (2.24 kg,11.2 moles, 93.2% w/w), 75% yield. ¹H-NMR (DMSO-d₆): δ 12.45 (s, 1H),7.72 (d, 2H, J=8 Hz), 7.37 (d, 2H, J=8 Hz), 2.50 (m, 1H), 1.94 (m, 1H),1.50 (m, 1H), 1.42 (m, 1H); ¹³C-NMR (DMSO-d₆): δ 173.51, 146.68, 132.27,126.93, 118.97, 108.85, 25.16, 25.04, 17.44; LC-MS (ESI): m/z 186 (M−1).

Intermediate E (1S,2S)-2-(4-Carbamoyl-phenyl)-cyclopropanecarboxylicacid

Intermediate D (4.46 kg, 22.0 moles, 92.5% w/w) was mixed in H₂O (40 L)at t_(jacket)=30° C. NaOH (2.25 kg, 28.1 moles, 50% w/w) diluted in H₂O(6 L) was added at such a rate so t_(inner) remained below 35° C. Thecharging vessel was rinsed with H₂O (1 L). If the pH was not >12, moreNaOH was charged in the same concentration as previously. Hydrogenperoxide (4.89 kg, 50.3 moles, 35% w/w) was added at a rate to maintaint_(inner) below 35° C. The charging vessel was rinsed with H₂O (1 L) andthe reaction slurry was left stirring for 0.5-1.0 h. At full conversionthe reaction mixture was cooled to t_(jacket)=0° C. and left stirringfor at least 0.5 h when the temperature was reached. The sodium salt ofIntermediate E was filtered off and washed with cold H₂O (2×7 L). Thesolid was slurry washed on the filter with NaHSO₄×H₂O (2.76 kg, 20.0moles) diluted in H₂O (35 L). The slurry was kept stirring att_(jacket)=0° C. for 1 h. If the pH was not <3.7, it was adjusted withNaHSO₄×H₂O in H₂O. The product was filtered off, washed with cold H₂O(3×14 L). Drying under vacuum at 40° C. gave Intermediate E (4.0 kg,18.2 moles, 93.4% w/w), 83% yield. ¹H-NMR (DMSO-d₆): δ 12.40 (s, 1H),7.94 (s, 1H), 7.79 (d, 2H, J=8 Hz), 7.32 (s, 1H), 7.23 (d, 2H, J=8 Hz),2.44 (m, 1H), 1.88 (m, 1H), 1.47 (m, 1H), 1.39 (m, 1H); ¹³C-NMR(DMSO-d₆): δ 173.83, 167.67, 143.94, 132.17, 127.68, 125.73, 25.21,24.67, 17.11; LC-MS (ESI): m/z 206 (M+1). The product was analyzed on achiral column with UV-detection using isocratic method (mobile phase:EtOH/Isohexane/TFA (15/85/0.1 v/v/v)) on Kromosil 3-Amycoat, 150×4.6 mm,3 μm particle size, giving an enantiomeric purity of >99% ee,R_(t)=13.40 min (isomer 1) and 22.22 min (isomer 2).

Intermediate F 1-Cyclobutylpiperazine×2HCl

N-Boc-piperazine (46 g, 0.25 moles), which is commercially availablefrom SAFC, was dissolved in EtOH (415 mL) at t_(jackei)=20° C. Aceticacid (140 mL) was added in one portion followed by the addition ofcyclobutanone (26.5 g, 0.37 moles). The charging vessel was rinsed withEtOH (25 mL) and the light yellow solution was left stirring att_(jacket)=20° C. for 1 h. NaBH(OAc)₃ (80 g, 0.36 moles, 95% w/w) wasadded in 20 portions is over 2 h. EtOH (25 mL) was used for rinsing. Thereaction mixture was left stirring for 2 h. At full conversion NAOH (296g, 3.70 moles, 50% w/w) diluted in H₂O (230 mL) was added at such a rateso t_(inner) remained below 35° C.

EtOH was distilled off under vacuum at t_(jacket)=45° C. toapproximately 650 mL. The water phase was extracted with toluene (550mL) at t_(jacket)=45° C. and the obtained organic phase was concentratedunder vacuum at t_(jacket)=45° C. to approximately 250 mL. The toluenesolution was diluted with 2-propanol (140 mL) at t_(jacket)=20° C. andH₂O (2.2 mL, 0.12 moles) was added. HCl in 2-propanol (82 mL, 0.49moles, 6M) diluted in 2-propanol (140 mL) was added over 30 min att_(jacket)=20° C. The reaction solution was heated to t_(jacket)=48° C.HCl in 2-propanol (164 mL, 0.99 moles, 6M) diluted in 2-propanol (276mL) was added over 2 h at t_(jacket)=46° C. The reaction solution waskept at t_(jacket)=48° C. for an additional 4 h before cooling tot_(jacket)=10° C. over 1 h. The product was filtered off and washed withcold 2-propanol (2×230 mL). Drying under vacuum at 40° C. gave 44 gIntermediate F (0.20 moles, 95.9% w/w), 80% yield. ¹H-NMR (DMSO-d₆): δ12.46 (s, 1H), 10.07 (s, 2H), 3.73 (m, 1H), 3.05-3.61 (m, 8H), 2.37 (m,2H), 2.14 (m, 2H), 1.70 (m, 2H); ¹³C-NMR (DMSO-d₆): δ 58.05, 44.67,39.59, 24.38, 13.18.

General Methods

¹H NMR spectra were recorded in the indicated deuterated solvent at 400MHz or 500 MHz. The 400 MHz spectra were obtained using a Bruker av400NMR spectrometer equipped with a 3 mm flow injection SEI ¹H/D-¹³C probehead with Z-gradients, using a BEST 215 liquid handler for sampleinjection, or using a Bruker DPX400 NMRor Bruker 500 MHz ultrashieldspectrometer equipped with a 4-nucleus probehead with Z-gradients.Chemical shifts are given in ppm down- and upfield from TMS. Resonancemultiplicities are denoted s, d, t, q, m and br for singlet, doublet,triplet, quartet, multiplet, and broad respectively.

Mass spectra (MS) were run using an automated system with electrospray(+ESI) ionization. Generally, only spectra where parent masses areobserved are reported. The lowest mass major ion is reported formolecules where isotope splitting results in multiple mass spectralpeaks (for example when chlorine or bromine is present).

LC-MS analyses were recorded on a Waters LCMS equipped with a WatersX-Terra MS, C8-column, (3.5 μm, 100 mm×3.0 mm i.d.). The mobile phasesystem consisted of A: 10 mM ammonium acetate in water/acetonitrile(95:5) and B: acetonitrile. A linear gradient was applied running from0% to 100% B in 4-5 minutes with a flow rate of 1.0 mL/min. The massspectrometer was equipped with an electrospray ion source (ESI) operatedin a positive or negative ion mode. The capillary voltage was 3 kV andthe mass spectrometer was typically scanned between m/z 100-700.Alternative, LC-MS HPLC conditions were as follows: Column: AgilentZorbax SB-C8 (5 μm, 50 mm×2 mm i.d) Flow: 1.0 mL/minGradient: 95% A to100% Bin 5 min. A=5% acetonitrile in water with 0.1% formic acid andB=acetonitrile with 0.1% formic acid, UV-DAD 210-400 nm. Alternative,LC-MS analyses were recorded on a Waters 2790 LCMS equipped with aPhenomenex Luna C18 (5 μm, 50×4.6 mm i.d.) The mobile phase systemconsisted of A: 10 mM ammonium formate (pH 4) in water and B:acetonitrile. A linear gradient was applied running from 95% to 5% B in5 minutes with a flow rate of 2.0 mL/min. The mass spectrometer wasequipped with an electrospray ion source (ESI) operated in a positive ornegative ion mode. The capillary voltage was 3 kV and the massspectrometer was typically scanned between m/z 100-700. Alternative,LC-MS analyses were recorded on a Agilent 1200 LCMS equipped with aZorbax SB C8 (3.5 μm, 150×4.6 mm i.d.) The mobile phase system consistedof A: 0.05% TFA in water and B: acetonitrile. A linear gradient wasapplied running from 10% to 90% B in 8 minutes with a flow rate of 1.0mL/min. The mass spectrometer was equipped with an electrospray ionsource (ESI) operated in a positive or negative ion mode. The capillaryvoltage was 3 kV and the mass spectrometer was typically scanned betweenm/z 100-700.

The compounds have been named using CambridgeSoft MedChem ELN v2.1,ACD/Name, version 8.08, software from Advanced Chemistry Development,Inc. (ACD/to

ABBREVIATION LIST

ACN: acetonitrile; aq: aqueous; br: broad; Bu: butyl; calcd: calculated;Celite®: brand of diatomaceous earth filtering agent, registered traderof Celite Corporation; d: doublet; dd: doublet of doublet; ddd: doubletof doublet of doublet; dddd: doublet of doublet of doublet of doublet;DMF: N,N-dimethyl formamide; DMSO: dimethyl sulfoxide; dq: doublet of isquartet; DSC: differential scanning calorimetry; dt: doublet of triplet;DVS: dynamic vapour sorption; EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; ESI: electrospray ionization; EtOAc: ethylacetate; EtOH: ethanol; Et: ethyl; FT-IR: Fourier-transform infrared;FT-Raman: Fourier transform Raman; g: gram; h: hour(s); ¹H NMR: protonnuclear magnetic resonance; HOBT: N-Hydroxybenzotriazole; HPLC: highpressure liquid chromatography; iPrOH: iso-propanol; L: liter; m:multiplet; M: molar; mL: milliliter; Me: methyl; MeOH: methanol; mg:milligram; 2-MeTHF: 2-methyl tetrahydrofuran; MHz: megahertz; min:minute(s); mmol: millimole; mol: mole; MS: mass spectrometry; MTBE:methyl tert-butyl ether; NaHCO₃: sodium bicarbonate; Pd/C: palladium oncarbon; ppm: parts per million; q: quartet; quin: quintet; rt: roomtemperature; s: singlet; sat: saturated; t: triplet; TEA: triethylamine;tBuOH: tert-butanol; td: triplet of doublet; TFA: trifluoroacetic acid;TGA=thermalgravimetric analysis; THF: tetrahydrofuran; UV=ultraviolet;XRPD=X-ray powder diffraction; and the prefixes n-, s-, i-, t- and tert-have their usual meanings normal, secondary, iso, and tertiary.

Pharmacology

Human Histamine H3 Binding Assay with the Agonist Radioligand[³H]-N-a-Methylhistamine

The H3 binding assay was used to evaluate the ability of a compound offormula (I) to inhibit [³H]-N-a-methylhistamine under the conditions asdescribed below: All binding assays were performed in a bufferconsisting of 20 mmol/L Hepes, 100 mmol/L NaCl. The pH was set at 7.4 atroom temperature. Liquid handling robots were used to prepare, in drugplates, 10 points dose response curves of the compound of formula (I)(3-fold serial dilutions, starting at 10 μmol/L). The assay, performedin 96-well plates, consisted of 100 μL, containing 20 μL of buffer alonefor total binding (column #1), 20 μL of imetit (5×) for the non specificbinding (column #2), 20 μL of the compound of formula (I) (5×) atvarying concentrations (column #3 to #12), plus 20 μL of[3H]-N-a-Methylhistamine (25 000 dpm/well, 1.5 nmol/L) in all wells andfinally 60 μL of membranes (20 μg of protein/well) mix is added to startthe reaction. Membranes and SPA beads (1000 μg/well) were mixed togetherand incubated for 30 minutes at room is temperature prior to the startof the assay. Eight wells (column #1) were used to define total bindingand 1 μmol/L imetit (eight wells, column #2) define the non-specificbinding. Plates were then mixed on an orbital mixer, incubated 90minutes at room temperature, and then read on a Trilux 384™ counter.

Guanosine 5′-O-(3-[³⁵S]thio)triphosphate [GTPgS] Binding Assay

[³⁵S]GTPγS binding assay was performed in a buffer consisting of 20mmol/L Hepes, 100 mmol/L NaCl, 10 mmol/L MgCl₂, 3 μg/mL saponine and 10μmol/L GDP. The pH was set at 7.4 at room temperature. Liquid handlingrobots were used to prepare, in drug plates, 10 points dose responsecurves of the compound of formula (I) (3-fold serial dilutions, startingat 1 μmol/L for hH3 receptors and 10 μmol/L for rH3 receptors). Theassay, performed in 96-well plates, consisted of 120 μL, containing 20μL of RαMH (EC80, antagonist mode), 20 μL the compound of formula (I) atvarying concentrations, 20 μL of the tracer [³⁵S]GTPγS (60000 dpm/well,0.2 nmol/L) and finally 60 μL of membranes (10 μg of protein/well forhH3) mix is added to start the reaction. Membranes, SPA beads (125μg/well) and GDP were mixed together and incubated for 30 minutes atroom temperature prior to the start of the assay. Eight wells were usedto define baseline and RαMH EC₈₀ (30 nmol/L for hH3 receptors) definethe positive control. Plates were then mixed (2 minutes) on an orbitalmixer, incubated 60 minutes at room temperature, and then read on aTrilux 384™ counter.

Results

A compound formula (I) showing pIC₅₀ values that were generated inaccordance with the assays described above, the inhibit specific bindingof [³H]-N-α-Methyl Histamine to the human H3 receptor (445 aa)) as7.9±0.060 (13 nmol/L) and the inhibition of H3 agonistR-α-Methyl-Histamine stimulated-[³⁵S]GTPγS binding as 8.5±0.14 (3.0nmol/L).

1. A crystalline form of compound (I),4-{(1S,2S)-2-[(4-cyclobutylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,


2. The crystalline form of compound (I) of claim 1, wherein said formhas an XRPD pattern (Cu Kα) with at least one peak at about 18.3°2Theta, when measured using radiation with a wavelength of about 1.54angstroms.
 3. The crystalline form of compound (I) of claim 1, whereinin that said form has an XRPD pattern (Cu Kα) with at least two peaks atabout 4.9 and about 18.3 °2Theta, when measured using radiation with awavelength of about 1.54 angstroms.
 4. The crystalline form of compound(I) of claim 1, wherein said form has an XRPD pattern (Cu Kα) with atleast three peaks at about 4.9, about 18.3 and about 20.4 °2Theta whenmeasured using radiation with a wavelength of about 1.54 angstroms. 5.The crystalline form of compound (I) of claim 1, wherein said form hasan XRPD pattern (Cu Kα) with at least four peaks at about 4.9, about18.3 about 19.6 and 20.4 °2Theta, when measured using radiation with awavelength of about 1.54 angstroms.
 6. The crystalline form of compound(I) of claim 3, wherein the XRPD pattern (Cu Kα) further comprises peaksat about 16, 4 and about 16.6, about 18.3 and about 19.6 °2Theta, whenmeasured using radiation with a wavelength of about 1.54 angstroms. 7.The crystalline form of compound (I) of claim 3, wherein the XRPDpattern (Cu Kα) further comprises a peak at about 5.3 °2Theta, whenmeasured using radiation with a wavelength of about 1.54 angstroms. 8.The crystalline form of compound (I) of claim 1, wherein said form hasan XRPD pattern (Cu Kα) with peaks at about 4.9, about 5.3, about 9.0,about 12.6, about 16.4, about 16.6, about 18.3, about 19.6, about 20.4,about 21.2, about 23.2 and about 24.6 °2Theta when measured usingradiation with a wavelength of about 1.54 angstroms.
 9. The crystallineform of compound (I) of claim 1, wherein the XRPD pattern is essentiallyas shown in FIG.
 1. 10. Thecrystalline form of compound (I) of claim 3,wherein the DSC thermogram comprises an endotherm at about 235° C. 11.The crystalline form of compound (I) of claim 10, wherein the DSCthermogram comprises an additional small endotherm at about 225° C. 12.The crystalline form of compound (I) of claim 3, wherein the DSCthermogram is essentially as shown in FIG.
 2. 13. The crystalline formof compound (I) of claim 1, which is substantially pure.
 14. Apharmaceutical formulation comprising a crystalline form of compound (I)as claimed in claim 1 in admixture with a pharmaceutically acceptableadjuvant, diluent and/or carrier.
 15. (canceled)
 16. (canceled) 17.(canceled)
 18. A method for the treatment of a disorder selected fromschizophrenia, narcolepsy, excessive daytime sleepiness, obesity,attention deficit hyperactivity disorder, pain, neuropathic pain,Alzheimer's disease, cognition deficiency, and cognition deficiencyassociated with schizophrenia, in a warm-blooded animal, comprisingadministering to said animal in need of such therapy a therapeuticallyeffective amount of a crystalline form of compound (I) according toclaim
 1. 19. The crystalline form of compound (I) of claim 8, whereinthe DSC thermogram comprises an endotherm at about 235° C.
 20. Thecrystalline form of compound (I) of claim 9, wherein the DSC thermogramcomprises an endotherm at about 235° C.
 21. The crystalline form ofcompound (I) of claim 8, wherein the DSC thermogram is essentially asshown in FIG.
 2. 22. The crystalline form of compound (I) of claim 9,wherein the DSC thermogram is essentially as shown in FIG. 2.